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Vol. 293, Issue 2, 569-577, May 2000
Department of Pharmacology and Toxicology, Faculty of Health
Sciences, Queen's University, Kingston, Ontario, Canada
The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the
action of glyceryl trinitrate (GTN) and the D-enantiomer of
isoidide dinitrate (IIDN), but not the L-enantiomer
(L-IIDN), in isolated rat aorta via inhibition of the
bioactivation of these prodrugs. Paradoxically, a vascular NAD(P)H
oxidase, which also is inhibited by DPI, has been proposed to generate
superoxide that quenches nitric oxide (NO) produced during GTN
biotransformation, and increased oxidase levels are proposed to
contribute to the phenomenon of organic nitrate tolerance. We examined
the effect of DPI on isolated rat aorta using an in vivo model of
organic nitrate tolerance. The EC50 values for GTN-,
D-IIDN-, and L-IIDN-induced relaxation of aorta
from GTN-tolerant rats were increased 4.5- to 7.5-fold. Treatment of
blood vessels with DPI (0.3 µM) increased the EC50 values
for GTN and D-IIDN by the same magnitude in control and
tolerant aortae, a result that would not be predicted if DPI and GTN
tolerance affected common targets. The expression of NADPH-cytochrome P450 reductase (CPR) during in vivo tolerance was assessed by NADPH-dependent cytochrome c reductase activity of
aortic microsomes, immunoblotting, and Northern analysis. By all three
determinants, CPR expression was unchanged in aorta from GTN-tolerant
rats. Superoxide dismutase-inhibitable NADPH-dependent
cytochrome c reductase activity (a measure of superoxide
generation) of tolerant rat aortic microsomes was not different from
that of controls. Superoxide dismutase-inhibitable NADH-dependent
cytochrome c reductase activity was detected only in
microsomes from tolerant animals. DPI caused a modest increase in the
sensitivity for relaxation by the NO donor DEA NONOate to an
equal extent in tolerant and nontolerant tissues, whereas the
superoxide scavenger, 4,5-dihydroxy-1,3-benzene disulfonic acid
(Tiron), had no effect on the sensitivity for relaxation by GTN. These
results would not be expected if tolerance-induced increases in
superoxide were a causative factor for the reduced relaxation response
in tolerance. We conclude that neither reduced flavoprotein-dependent
metabolic activation of organic nitrates, such as that mediated by CPR,
nor increased superoxide due to increased NAD(P)H oxidase activity can
account for the development of in vivo tolerance to GTN.
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